Mechoulam et al. have reported that two cannabinoid receptors have been identified: CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2 present outside the CNS, in peripheral organs including peripheral nerve terminals [Mechoulam et al., Proc. Nat. Acad. Sci., U.S., 96, 14228-14233]. Cannabis sativa preparations have been known as therapeutic agents against various diseases for millenia. The native active constituent, Delta 9-tetrahydrocannabinol (delta-9-THC) is prescribed today under the generic name Dronabinol, to treat vomiting and for enhancement of appetite, mainly in AIDS patients.
Separation between the therapeutically undesirable psychotropic effects from the clinically desirable ones, however, has not been reported with agonists that bind to cannabinoid receptors. THC, as well as the two major endogenous compounds identified so far that bind to the cannabinoid receptors, anandamide and 2-arachidonylglycerol (2-AG) produce most of their effects by binding to both the CB1 and CB2 cannabinoid receptors. The CB1 receptor is present in the CNS, and to a lesser extent in other tissues. The CB2 receptor is not present in the CNS, but mostly in peripheral tissue associated with immune functions, including macrophages and B cells, as well as in peripheral nerve terminals. While the effects mediated by CB1, mostly in the CNS, have been thoroughly investigated, those mediated by CB2 are not well defined.
Inhibition of gastrointestinal activity has been observed after administration of Delta 9-THC or of anandamide. This effect has been assumed to be CB1-mediated since the specific CB1 antagonist SR 141716A blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB2-mediated component.
Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension. Anandamide and 2-AG, produced by macrophages and platelets, respectively, may mediate this effect.
The hypotension in hemorrhaged rats was prevented by the CB1 antagonist SR 141716A. Recently the same group found that anandamide-induced mesenteric vasodilation is mediated by an endothelially located SR 141716A-sensitive “anandamide receptor,” distinct from the CB1 cannabinoid receptor, and that activation of such a receptor by an endocannabinoid, possibly anandamide, contributes to endotoxin-induced mesenteric vasodilation in vivo. The highly potent synthetic cannabinoid HU-210, as well as 2-AG, had no mesenteric vasodilator activity. Furthermore it was shown that mesenteric vasodilation by anandamide apparently has 2 components, one mediated by a SR 141716-sensitive non-CB1 receptor (located on the endothelium) and the other by an SR 141716A-resistant direct action on vascular smooth muscle.
The production of 2-AG is enhanced in normal, but not in endothelium-denuded rat aorta on stimulation with carbachol, an acetylcholine receptor agonist. 2-AG potently reduces blood pressure in rats and may represent an endothelium-derived hypotensive factor.
Anandamide attenuates the early phase or the late phase of pain behavior produced by formalin-induced chemical damage. This effect is produced by interaction with CB1 (or CB1-like) receptors, located on peripheral endings of sensory neurons involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the skin, also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB1 or CB2. Its analgetic activity is blocked by the specific CB2 antagonist SR 144528, though not by the specific CB1 antagonist SR 141716A. Hence a CB2-like receptor was postulated.
U.S. Pat. No. 5,434,295 discloses a family of novel 4-phenyl pinene derivatives, and teaches how to use those compounds in pharmaceutical compositions useful for treating various pathological conditions associated with damage to the central nervous system. U.S. Pat. No. 4,282,248 discloses additional pinene derivatives. These patents do not mention that any of the disclosed compounds are selective for peripheral cannabinoid receptors.
Several synthetic cannabinoids have been shown to bind to the CB2 receptor with a higher affinity than to the CB1 receptor. Most of these compounds exhibit only modest selectivity. One of the described compounds, a classical THC-type cannabinoid, L-759,656, in which the phenolic group is blocked as a methyl ether, has a CB1/CB2 binding ratio>1000. The pharmacology of those known agonists has yet to be described.
Certain tumors, especially gliomas, express CB2 receptors. Guzman and coworkers have shown that delta-9-tetrahydrocannabinol and WIN-55,212-2, two non-selective cannabinoid agonists, induce the regression or eradication of malignant brain tumors in rats and mice [Guzman, et al., Nature Medicine 6, 313-319, (2000)]. The rat glioma C6 expresses the CB2 receptor and, on the basis of studies with CB1 and CB2 selective antagonists, it has been proposed that activation of either of the two receptors may trigger apopotosis.
Thus, there is a need for selective peripheral cannabinoid receptors and particularly for specific agonists of the peripheral cannabinoid receptor CB2. The present invention now satisfies that need.